The present invention relates to a novel crystal habit of 2-n-butyl-4-spirocyclopentane-1-[(2xe2x80x2-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one of formula: 
This compound and its method of preparation were disclosed for the first time in European patent EP 454 511. The compound of formula (I) is an angiotensin II antagonist which is useful in the treatment of cardiovascular diseases such as hypertension, cardiac insufficiency, cardiac arrhythmia, in the treatment of diseases of the central nervous system, in the treatment of glaucoma and diabetic retinopathy and in the treatment of renal insufficiency and diabetic nephropathy.
The common name of the compound of formula (I) is irbesartan and the term irbesartan is used in this description and in the claims to refer to the compounds of formula (I).
European patent application EP 708 103 discloses the existence of 2 crystalline forms of irbesartan:
one, known as form A, is the one obtained by crystallization in a solvent containing less than about 10% by volume of water,
the other, known as form B, is obtained by crystallization in a water-miscible solvent containing more than about 10% water.
Each of these two forms is characterized by a specific X-ray diffraction profile.
Patent application EP 708 103 discloses that form B is a tautomeric form.
Patent application EP 708 103 indicates that irbesartan in the form A is in the form of stable, non-hygroscopic needles of high electrostatic nature. Hereinbelow in the present description, the term xe2x80x9cacicular habitxe2x80x9d denotes this crystalline form of the irbesartan form A.
It also been found that these crystals of acicular habit are difficult to filter and to dry and that they display poor flowability.
A novel crystal habit of the form A has now been found, characterized in that the ratio between the length and the width of the crystals is between 1:1 and 10:1, preferably between 1:1 and 5:1. This novel crystal habit of the form A of irbesartan will be defined by the term xe2x80x9cbrick habitxe2x80x9d of irbesartan hereinbelow in the present description.
A subject of the present invention is also processes for obtaining irbesartan crystals of form A which have the novel crystal habit according to which the ratio between the length and the width of the crystals is between 1:1 and 10:1, preferably between 1:1 and 5:1.
The higher this ratio, the longer are the needles relative to their width, and thus an improvement in this ratio means a decrease of the said ratio. It is preferable for this ratio to decrease such that it is between 1:1 and 10:1, preferably between 1:1 and 5:1.
The improvement of this ratio means that the crystals have less of a tendency to break or to aggregate when they are wet, they can be filtered and dried faster, and they are easier to handle when they are dry.
The processes according to the invention have no effect on the polymorphism.
The irbesartan crystals in the brick habit have the physicochemical characteristics described below.
The powder X-ray diffraction profile (diffraction angle) was established with a Siemens D 550 TT diffractometer, and the significant lines are given in Table I below:
This diffraction profile is that of the form A of irbesartan disclosed in EP 708 103.
The chargeability of the powder is measured by tribogeneration: the powder is subjected to a strong vibration during which it becomes charged on itself, and is then transferred into a Faraday cage connected to a very sensitive electrometer. The chargeability measured varies between 0 and xe2x88x9210 nanocoulomb/g. By way of comparison, the crystals of irbesartan in acicular form A have a chargeability, measured by the same process, of between xe2x88x9230 and xe2x88x9240 nanocoulomb/g.
The packing density of the irbesartan crystals having the new crystal habit, measured using a Hosokawa machine (180 gravity drops), is about 0.5 kg m3, whereas that of the crystals of the acicular form A is about 0.35 kg/M3.
The flowability index is calculated by the Carr method (R. Carr: Chemical Engineering, Jan. 18, 1965, page 163-168) and takes into account the results of four experimental values: compressibility, angle of repose, spatula angle and cohesion. This index is about 30 for the crystals of brick habit, whereas it is about 10 for the crystals of acicular habit.
It is found that the resistivity, the minimum inflammation energy, the minimum inflammation temperature, the results of the friction test and gravity of the explosion, measured in a 20-liter sphere, are similar for the two crystal habits of the form A of irbesartan.
The fact that the irbesartan crystals of brick habit are of reduced chargeability, i.e. they have a reduced tendency to store electrostatic charges, means that these crystals can be handled more easily and more safely.
The 50% increase in the packing density and in the flowability index of the brick habit with respect to the acicular habit represents an improvement which is reflected both in the chemical processability of the product and in their use for their preparation of pharmaceutical forms.
According to the present invention, the irbesartan of brick habit can be prepared using a process characterized in that a crystalline suspension of irbesartan of acicular habit form A is subjected to at least one sonication episode and at least one temperature oscillation episode.
Thus, the sonication episode can be either followed or preceded by the temperature oscillation episode.
It is also possible to envisage the sonication episode being carried out simultaneously with the temperature oscillation episode. According to the invention, a sonication episode can also be carried out between 2 phases of temperature oscillation.
Furthermore, the sonication and/or temperature oscillation episodes can be repeated independently of each other.
Preferably, a sonication episode is preceded by a temperature oscillation episode and more particularly a sonication episode is carried out between 2 temperature oscillation episodes.
The term xe2x80x9ccrystalline suspensionxe2x80x9d used in the present description refers to an irbesartan suspension prepared according to methods that are known to those skilled in the art. For example, the crystalline suspension can be prepared by growing irbesartan crystals in an organic solvent, for example an alcohol such as isopropanol, to prepare a supersaturated irbesartan solution, and cooling to a temperature at which the supersaturation is between 0% and 50%. The supersaturated solution is then seeded with 1% to 10% of irbesartan seed crystals of brick habit, the seed crystals originating from a previous batch. However, the seeds may also be generated by repeatedly subjecting the crystalline suspension to temperature oscillation and sonication episodes until crystals of brick habit are obtained. The seeded solution is then cooled to room temperature to form the crystalline suspension. The said crystalline suspension is then used according to the invention.
According to the present invention, a sonication episode consists in subjecting the crystalline suspension to a sonication energy whose frequency is from about 16 kHz to 10 MHz. It appears that the sonication episode limits the growth according to the length of the needles by breaking them and modifies the nature of the crystal surfaces such that the zones capable of accumulating the electrostatic charges are reduced. Sonication methods may be used either batchwise or semi-continuously or continuously.
For the batchwise sonication, an ultrasound probe is inserted into the crystalline suspension placed in a crystallizer.
The sonication episode can also be carried out continuously or semi-continuously by pumping the crystalline irbesartan suspension through a sonication cell at a flow rate of from about 10 liters/min/KW to liters/min/KW; with a pressure of from 0 psig to 100 psig; with an energy of about from 10 000 joules/liter to 30 000 joules/liter and at a frequency of about from 16 kHz to 10 MHz. Preferably, the flow rate is between 16 liters/min/KW and 18 liters/min/KW; the pressure is between 0 psig and 20 psig; the energy is between 16 000 and 25 000 joules/liter and the frequency is about 20 kHz.
The above sonication parameters such as the flow rate, the pressure and the frequency vary as a function of the expected result in terms of ratio between the length and the width of the crystals prepared.
The temperature oscillation episode comprises a heating phase and a cooling phase. According to the invention, it comprises at least one heating phase and at least one cooling phase in any order. It is preferable for a heating phase to be combined with a cooling phase, and even for the said heating phase to precede the said cooling phase. It is probable that the temperature oscillation contributes towards controlling the correct distribution of the size of the particles; in particular, it tends to dissolve the finer particles and to make the coarser particles grow.
The temperature oscillation is carried out by heating and cooling a crystalline suspension to predetermined temperatures. The heating phase is performed by heating up to about 20xc2x0 C. to 100xc2x0 C. Preferably, the heating phase is carried out at a temperature such that about 15% to 25% is dissolved in 60 minutes, more particularly about 20% of the crystals are dissolved in 60 minutes. The cooling phase of the temperature oscillation episode is generally carried out between 100xc2x0 C. and xe2x88x9220xc2x0 C. Preferably, the cooling phase is carried out at a temperature of between xe2x88x925xc2x0 C. and 20xc2x0 C. for about 0 to 60 minutes; more particularly between 0 and 5xc2x0 C. for about 0 to 60 minutes.
It should be noted that the temperature selected for the cooling phase of the temperature oscillation episode is less than the temperature selected for the corresponding heating phase. The heating and cooling phases can be repeated independently, as many times as necessary, and the specific parameters may be modified to obtain the desired product.
For example, it is possible to extend the heating phase and shorten the cooling phase to generate shorter crystals or alternatively it is possible to shorten the heating phase and extend the cooling phase to generate larger crystals. The number of heating and cooling phases also depends on the desired result. In general, if the number of heating and cooling phases increases, the appearance of the crystals improves and the ratio between the length and the width tends towards 1:1.
Controlling the sonication and temperature oscillation parameters makes it possible to control the size distribution of the particles and the ratio between the length and the width of the final crystals.
The process described above for modifying the crystal habit of irbesartan using sonication presents difficulties in industrial implementation. Specifically, the efficacy of the ultrasound emitter decreases beyond a few centimetres from the said emitter; furthermore, when working continuously, this efficiency decreases if the speed of passage of the crystalline suspension treated increases.
Also, to treat large volumes, the application time is very long. Moreover, high-power ultrasound causes premature wear of the metals and welds of the apparatus used.
Another process for modifying the crystal habit of the irbesartan form A uses wet grinding, i.e. the mechanical shearing of the crystals of acicular habit to convert them into crystals of brick habit. This process has the advantage of being readily applicable to the treatment of industrial amounts of product.
Thus, according to another of its aspects, the present invention relates to a process for preparing irbesartan of brick habit, characterized in that it contains the steps consisting in:
a) preparing a solution of irbesartan form A in an alcohol, under concentration and temperature conditions which allow the total solubility of the irbesartan;
b) cooling the said solution to a temperature selected as a function of the concentration of the solution, such that the solution is in the metastable zone;
c) seeding with irbesartan crystals of brick habit;
d) cooling the irbesartan solution to a temperature of between about 20xc2x0 C. and 5xc2x0 C.;
e) subjecting the crystalline suspension thus formed to a mechanical shearing using a shearing machine;
f) heating the crystalline suspension to a temperature of between about 40xc2x0 C. and 60xc2x0 C. to dissolve the fine particles;
g) cooling the crystalline suspension to a temperature of between about 20xc2x0 C. and 5xc2x0 C.;
h) filtering off the crystals of brick habit thus formed.
According to the present invention, a solution of irbesartan in alcohol, for example ethanol or, preferably, isopropanol, is used.
FIG. 1 indicates, for a solution of irbesartan form A in isopropanol, the conditions for total solubility, as a function of the concentration in g/liter and of the temperature in xc2x0 C. It also indicates the limits of the metastable zone for a solution containing 25 g/liter to 70 g/liter of irbesartan.
Thus, for a solution of irbesartan in isopropanol containing about 50 g/liter to 70 g/liter, the seeding temperature ranges from 45xc2x0 C. to 80xc2x0 C. in order for the solution to remain in the metastable zone.
The irbesartan solution can be seeded with irbesartan crystals of brick habit at any point in the cooling of the solution, when this solution is in the metastable zone. The seeding temperature is between 25xc2x0 C. and 80xc2x0 C., depending on the concentration of the solution. The proportion of seed crystals incorporated may be between 1% and 25%, preferably between 10% and 20%. After seeding, the temperature can be kept constant for a period of between a few minutes and 2 hours, preferably for half an hour to one hour.
In steps b) and d), the cooling is advantageously carried out at a uniform cooling rate of about 5xc2x0 C. to 20xc2x0 C. per hour, preferably in the region of 10xc2x0 C. per hour.
In step e), the mechanical shearing is preferably carried out with a machine having a spin speed of about 10 000 to 15 000 rpm.
Machines having such characteristics are, for example, of the Turrax(copyright) type, sold by IKA-Werke (Germany). Some of these machines are suitable for treating industrial amounts ranging up to the point of allowing a flow rate of 100 m3/hour. For the process according to the invention and at an industrial stage, a flow rate of between about 500 liters/hour and 4 m3/hour is preferred, in a 2 m3 reactor.
The mechanical shearing in step e) can be carried out either by placing the shearing machine in the reactor containing the crystalline suspension, or by passing the crystalline suspension continuously into the shearing machine. In this case, the flow rate of the machine is adjusted as a function of the ratio between the length and the width which is desired for the crystals of brick habit formed.
Optionally, in order to improve the yield of crystals of brick habit, steps e), f) and g) can be repeated before filtering off the crystals of brick habit formed and drying them.
A subject of the present invention is also pharmaceutical compositions containing, as active principle, irbesartan of brick habit, i.e. irbesartan of form A, having a novel crystal habit. These pharmaceutical compositions may be prepared according to the discription of patent application EP 747 050.
The formulations prepared with the brick habit can contain up to about 80% by weight of irbesartan or about 85% by weight of irbesartan combined with a diuretic agent, for example hydrochlorothiazide. These formulations may be prepared industrially, for example in the form of tablets or gel capsules, according to known processes, for example by wet granulation, dry granulation or direct tabletting.
By tabletting, tablets of uniform weight are obtained continuously, these tablets having physical properties that are suitable for industrial development.